Intimal hyperplasia is the increase in the number of cells between the endothelium and internal elastic lamina of a blood vessel, particularly in the intimal layer found there, or in an artery. Intimal hyperplasia is often caused by smooth muscle cell (SMC) proliferation in the blood vessel wall.
When intimal hyperplasia occurs, de novo thickening of the intimal layer or of the vessel wall, i.e. stenosis, may result. Thus, the blood vessel may become occluded.
Also, when an obstruction in a blood vessel has been cleared, intimal hyperplasia occurring after surgery may lead to the artery's becoming occluded again. This is known as restenosis.
Proliferation of arterial smooth muscle cells commonly occurs when a blood vessel, e.g. an artery, is deformed or disturbed during surgery. For example, intimal hyperplasia can lead to de novo stenosis following bypass grafts in which a vein is anastomosed to an artery, and following surgical anastomosis in general. Two examples of surgical procedures which can give rise to stenosis are coronary bypass grafts and above-knee femoro-popliteal arterial bypass grafts.
Similarly, restenosis can occur following balloon angioplasty procedures used to clear obstructions in blood vessels, for example balloon angioplasty procedures.
Intimal hyperplasia, whether it leads to stenosis or restenosis, remains a major problem after various surgical procedures.
Atherosclerotic cardiovascular disease is the leading cause of death in Europe and North America and prompts a highly significant morbidity consequent upon occlusion of the arterial lumen, either preventing or reducing blood flow, thrombosis superimposed upon a plaque, with possible distal embolisation, arterial wall weakening, leading to aneurysmal dilation and eventual rupture. Dependant upon site and disease distribution, several options for treatment exist, with arterial bypass grafting the most common surgical intervention. For coronary artery disease, this has now become the most common surgical procedure of all in the United States with >200,000 operations performed each year since 1990 and with >20,000 operations performed each year in the United Kingdom. In the aorta, renal, mesenteric and peripheral vessels, the burden of surgical bypass procedures continues to increase, with operation rates in the United States and Europe of 35-70 per 100,000 population. In combination, the number of surgical bypass procedures performed each year approximates one million.
In the first 24 months following surgery, a very significant number of arterial bypass grafts fail (occlude). Quoted values range from 20% to 30%. This means that for all cardiac and peripheral arterial bypass procedures performed each year in the United Kingdom (approximately 25,000-30,000), between 6,000 and 7,000 may be expected to fail, within two years. Failure rates for ‘re-do’ procedures are even higher. Such is the financial cost of failure that, in the United States, it has been calculated that even a modest decrease in failure rates following coronary procedures, from 33% to 25%, might save up to $750 million from the healthcare budget.
There are three main causes for graft failure within five years from surgery. The first is recognised to occur early, within 30 days of the operation (<5%), and represents technical error (e.g. poor anastomotic technique). Later failure, after 24 months, is generally as a result of progression of the original atherosclerotic process. However, it is those grafts that occlude between one and 24 months that form the majority of failures (<70%). In these cases, it is SMC intimal hyperplasia that is responsible for progressive narrowing, i.e. stenosis, of the arterial lumen, resulting eventually in complete occlusion. Typically, the SMC intimal hyperplasia is sited around the distal arterial anastomosis and the native vessel wall opposite the anastomosis. It is thus a primary pathology at this site and not restenosis at a site of previous intimal hyperplasia as might occur following angioplasty. SMC intimal hyperplasia can occur at the more proximal arterial anastomosis and along the graft itself
Restenosis after angioplasty can lead to even higher failure rates, from 20 to 50% in the first 6 months following the angioplasty. Stenosis and restenosis both remain major problems after surgery.
To date, numerous methods of treating or preventing intimal hyperplasia have been tested, but none has been clinically satisfactory.
Vascular endothelial growth factor (VEGF) is a naturally-occurring protein. In humans, at least four forms exist, of 121, 165, 189 and 206 amino acids. The cDNA and amino acid sequences of the four forms of human VEGF are given in Houck et al, Molecular Endocrinology (1991) vol 5, No. 12, pages 1806-1814. A partial genomic sequence is also given. The cDNA sequence of human VEGF is also given in Leung et al, Science (1989) 246:1306-1309, together with the bovine VEGF cDNA sequence.
These four forms are referred to herein as VEGF-121, VEGF-165, VEGF-189 and VEGF-206. It should be understood that this numbering refers to the number of amino acids in the mature protein in each case. The translated protein also includes a 26 amino acid presequence which, in nature, is cleaved during intracellular processing.
VEGF is known to play a role in angiogenesis, where it stimulates the division of vascular endothelial cells (EC), increases endothelial permeability and acts as an endothelial “survival factor” in retinal vessels. For example, VEGF, in the form of recombinant protein or when expressed from a plasmid, can induce the development of new blood vessels when injected intra-arterially into ischaemic limbs. This property has led to its use in repairing arteries whose endothelia have been damaged during surgery. Thus, Asahara et al, Circulation (1995) 91: 2793, delivered VEGF, via a cannula, to the interior of rat carotid arteries following angioplasty that had denuded the endothelium of the artery; it was found that VEGF stimulated the reendothelialisation of the artery which, in turn, appeared to contribute to suppression of intimal hyperplasia.
VEGF protein and gene are disclosed in WO-A-9013649, and their use for treating trauma of the vascular epithelium, diabetic ulcers and blood vessel wounds is proposed. VEGF fragments are described in WO-A-9102058, and their use in angiogenesis and re-endothelialisation of inner vascular surfaces, e.g. in the treatment of ulcers.
GB-A-2298577 discloses a non-restrictive, porous, external stent for arteriovenous bypass grafting procedures. This stent has beneficial effects on luminal size and on medial and intimal thickening.
WO-A-9423668 discloses a device for the local delivery of an agent into a blood vessel, including a reservoir formed between two elements thereof. Its use requires implantation, i.e. cutting through the vessel and then securing the device to the vessel walls. The device is partially porous. The reservoir is in direct contact with luminal blood flow. This involves the risk of infection.
U.S. Pat. No. 3,797,485 discloses a device for delivering a drug to the adventitial surface of a blood vessel. It is provided with permanent walls and transcutaneous tubes for the delivery of drug in liquid form. The intention is that the drug should pass to another site.